A novel approach in diagnosing multiple dentigerous cysts using CBCT illustration indicative of Mucopolysaccharidosis VI - a case report.

Mucopolysaccharidosis VI is a genetic disorder affecting multiple organs with sundry clinical presentations. The main etiological factor reflects the disturbances in mucopolysaccharide metabolism leading to deposition of acid mucopolysaccharide in various tissues. The pathognomonic features of the disease include a large head, short neck, corneal opacity, open mouth associated with an enlarged tongue, enlargement of the skull, and long anteroposterior dimension with unerupted dentition, dentigerous cyst-like follicles, condylar defects, and gingival hyperplasia. An 18-year-old boy with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is described in this article, emphasizing the oral manifestations and radiographic illustration of lesions in the jaws. It also emphasizes the essential role of cone-beam computed tomography to identify and analyze multicentric pathologies in the jaws.

Mucopolysaccharidosis type VI: case report with first neonatal presentation with ascites fetalis and rapidly progressive cardiac manifestation.

BACKGROUND: The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease. CASE PRESENTATION: A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age. CONCLUSIONS: We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.

MRI findings of the cervical spine in patients with mucopolysaccharidosis type VI: relationship with neurological physical examination.

AIM: To describe the magnetic resonance imaging (MRI) findings of the cervical spine of patients with mucopolysaccharidosis type VI (MPS VI) and correlate them with clinical manifestations. MATERIALS AND METHODS: This is a cross-sectional study involving 12 patients with MPS VI. A limited neurological examination was undertaken in each patient including Tinel's test, assessment of muscle tone, and the evaluation of deep tendon reflexes. Additionally, each patient underwent cervical spine MRI to evaluate platybasia, odontoid dysplasia, periodontoid soft-tissue thickening, spinal canal stenosis, myelopathy, basilar invagination, platyspondyly, and reduction of nasopharyngeal airway. RESULTS: Nine patients were male (75%). The average age was 12.5 (±3.5 years). Tinel's test was negative in all patients. No muscle tone abnormalities were observed. Approximately 48% of the tested reflexes were considered abnormal, 10 of which (8.3%) were pathological occurring in five different patients (41.6%). At MRI, all patients showed periodontoid soft-tissue thickening and cervical spinal stenosis; six showed spinal cord compression and two showed myelopathy. Odontoid hypoplasia and basilar invagination were observed in nine patients. All patients with cervical stenosis on MRI had abnormal reflexes; however, only two of the six patients with evidence of cord compression on MRI had abnormal reflexes on clinical examination. CONCLUSIONS: The present study of 12 patients with MPS VI demonstrated that a normal neurological examination cannot confidently exclude potential cord compression in patients with this condition. MRI may aid in the timely identification of cervical spine abnormalities, and potentially play a role in lessening morbidity and mortality in patients with MPS.

Diagnosis of Attenuated Mucopolysaccharidosis VI: Clinical, Biochemical, and Genetic Pitfalls.

Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur.

Hemifacial Spasm in Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome).

Background: Hemifacial spasms are involuntary contractions of the muscles of one side of the face. Case Report: Here, we report a 5-year-old female patient with a significant past medical history, including mucopolysaccharidosis type VI, who also presented with hemifacial spasms. Further investigations showed narrowing of skull foramina and hydrocephalus, but no compression of the facial nerve. Carbamazepine was given to the patient, which caused cessation of the spasms. Discussion: Currently, there is no literature discussing the relationship between hemifacial spasms and mucopolysaccharidosis type VI; we have proposed that mucopolysaccharide deposits or dural thickening may contribute to nerve irritation.

Cervical cord compression in mucopolysaccharidosis VI (MPS VI): Findings from the MPS VI Clinical Surveillance Program (CSP).

OBJECTIVES: To gain insight into the frequency, age of onset, and management of cervical cord compression in mucopolysaccharidosis VI (MPS VI). METHODS: Cervical spine magnetic resonance imaging (MRI) data and/or cervical decompression surgery data collected between 30 June 2005 and 1 September 2015 were analyzed from subjects enrolled in the MPS VI Clinical Surveillance Program (CSP) (ClinicalTrials.gov: NCT00214773), an ongoing multicenter, observational, retrospective and prospective registry. RESULTS: Of 213 subjects enrolled in the CSP, 134 (62.9%) had at least one documented cervical spine MRI assessment. An additional four subjects were identified through surgery records alone to yield a study population comprising 138 subjects (mean age at enrollment =15.1years; age range=0.80-65.0years). Cervical cord compression was documented in 101 (75.4%) of the 134 subjects with ≥1 MRI assessment, the majority (95.0%) by the time of the first recorded MRI. In general, subjects with cervical cord compression had significantly lower height Z-scores compared to those without cervical cord compression (p<0.0001); nevertheless, a few subjects of taller stature had documented cervical cord compression at a young age. Most subjects >20years of age (31/33, 93.9%) presented with cervical cord compression. There was an insufficient number of subjects with both pre- and post-enzyme replacement therapy (ERT) MRI data to determine any association between ERT and cervical cord compression. Surgical decompression was performed on 58 subjects (42.0%), with mean age at first surgery of 13.1years. Decompression plus stabilization procedures accounted for 12.1% of surgeries. Eight subjects (13.8%) underwent reoperation. Complications during or following surgery were reported in 3 subjects, with anesthesia-related complications resulting in two deaths. CONCLUSIONS: All individuals with MPS VI are at high risk of developing cervical cord compression at an early age. Routine MRI assessments should be initiated from the time of MPS VI diagnosis. The perioperative management of MPS VI patients can be challenging. This study contributes to the understanding of the natural history of MPS VI.

Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

BACKGROUND: Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI. METHODS: Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and ß-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia. RESULTS: At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and ß-glucuronidase but all were significantly different than control animals (for each, p<0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals (p<0.001). There was no significant difference in corneal clouding scores among treated and untreated animals. CONCLUSIONS: There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions.

Mucopolysaccharidosis IVA (Morquio A syndrome) and VI (Maroteaux-Lamy syndrome): under-recognized and challenging to diagnose.

OBJECTIVE: Mucopolysaccharidosis IVA (MPS IVA, or Morquio A syndrome) and VI (MPS VI, or Maroteaux-Lamy syndrome) are autosomal recessive lysosomal storage disorders. Skeletal abnormalities are common initial presenting symptoms and, when recognized early, may facilitate timely diagnosis and intervention, leading to improved patient outcomes. Patients with slowly progressing disease and nonclassic phenotypes can be particularly challenging to diagnose. The objective was to describe the radiographic features of patients with a delayed diagnosis of MPS IVA or VI. MATERIALS AND METHODS: This was a retrospective study. The records of 5 MPS IVA and 3 MPS VI patients with delayed diagnosis were reviewed. Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias. RESULTS: An important common theme in these cases was the appearance of multiple epiphyseal dysplasia (MED) with epiphyseal changes seemingly confined to the capital (proximal) femoral epiphyses. Very few patients had the skeletal features of classical dysostosis multiplex. CONCLUSIONS: Radiologists should appreciate the wide phenotypic variability of MPS IVA and VI. The cases presented here illustrate the importance of considering MPS in the differential diagnosis of certain skeletal dysplasias/disorders, including MED, some forms of spondylo-epiphyseal dysplasia (SED), and bilateral Perthes-like disease. It is important to combine radiographic findings with clinical information to facilitate early testing and accurate diagnosis.

Advantages of early replacement therapy for mucopolysaccharidosis type VI: echocardiographic follow-up of siblings.

Mucopolysaccharidosis type VI (Marateaux-Lamy syndrome) is an autosomal recessive disorder caused by deficient activity of the enzyme N-acetylgalactosamine-4-sulphatase (arylsulphatase B). Cytoplasmic vacuoles full of dermatan sulphate are observed in endothelial cells, myocyte, and fibroblasts, compromising the function of cardiovascular structures and contributing significantly towards morbidity and mortality. The primary objective of this study was to assess the advantages of early replacement therapy with recombinant human arylsulphatase B through the echocardiographic follow-up of sisters who started treatment at quite different ages: one at 9 years and the other at 1 year and 7 months. The older sibling showed striking mitral and aortic valve compromise when she was only 2 years old and finally needed cardiac surgery at the age of 8, even before starting enzyme replacement. Differently, the younger one has developed only mild mitral and aortic lesions throughout the follow-up period of 3 years. The two siblings had left ventricle cardiomyopathy, but partial reverse remodelling was induced by enzyme replacement therapy in both cases. The younger sibling has never received any cardiovascular drugs, whereas the older one has been using ß-blockers and diuretics in addition to enzyme therapy to cope with heart failure. Comparing the outcomes of these two sisters with a very aggressive phenotype of mucopolysaccharidosis type VI, the conclusion was that early onset of therapy may slow down the disease progression and prevent severe cardiac lesions to be established. Moreover, patients' compliance is essential for the success of treatment, as sequential echocardiographic evaluation demonstrated worsening of some cardiac lesions whenever infusions were missed.

Attenuated osteoarticular phenotype of type VI mucopolysaccharidosis: a report of four patients and a review of the literature.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome, MPS VI, OMIM 253200) is caused by mutations in the gene coding for N-acetylgalactosamine-4-sulfatase (4-sulfatase, arylsulfatase B, ARSB, EC 3.1.6.12), a lysosomal enzyme involved in the degradation of dermatan sulfate (DS). The clinical presentation of MPS VI varies greatly with respect to age of onset and rate of disease progression. This report focuses on the attenuated form of MPS VI, which can go unrecognized for years and often presents with atypical signs or symptoms. We described a cohort of MPS VI patients (n = 4) heterozygous for the p.Y210C mutation who had a significant osteoarticular involvement at the onset of their disease and who were diagnosed years or even decades later. We have also reviewed the literature (n = 36). Two types of attenuated MPS VI phenotypes could be distinguished: osteoarticular and cardiac. The majority of MPS VI patients reported so far as relatively attenuated presented with an essentially osteoarticular phenotype associated with the p.Y210C mutation. Patients homozygous for the p.R152W mutation presented with a cardiac phenotype, which, despite fulfilling the generally used criteria for attenuated phenotype, may lead to fast disease progression and abrupt death. The knowledge of natural history and genotype-phenotype correlation may help in developing a tailored therapy potentially using enzyme replacement therapy with substrate reduction therapy or chaperones.

Attenuated mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) due to homozygosity for the p.Y210C mutation in the ARSB gene.

We describe the case of a boy recently diagnosed with an attenuated form of mucopolysacchararidosis VI (MPS VI, Maroteaux-Lamy syndrome). The Y210C mutation has not been described previously in the homozygous state, although this is a common ARSB mutation. His phenotype is essentially musculoskeletal. Urine screening tests based on measuring total GAG may miss this presentation as total GAGs were not elevated in the patient (although the electrophoresis pattern was clearly abnormal). In this phenotype the benefit of ERT remains to be established.

Central corneal thickness in mucopolysaccharidosis II and VI.

OBJECTIVE: To describe the ultrasonographically detected central corneal thickness (CCT) in patients with Type II and VI mucopolysaccharidosis (MPS) and its impact on applanation tonometry and glaucoma detection. METHODS: Twenty-eight patients with MPS (19 MPS II, nine MPS VI) underwent pachymetric investigation of CCT. Additionally, ultrasound measurements of axial length of the globe, slit-lamp evaluation with semiquantitative grading of corneal clouding, applanation tonometry, and assessment of refractive error were performed. RESULTS: Median average corneal thickness was 534.5 microm (range, 491.5-579.0 microm) in the MPS II and 547.0 microm (range, 492.5-693.05 microm) in the MPS VI group. CCT depended on degree of corneal clouding and patients' age, but did not correlate with intraocular pressure, refractive error, axial length, or MPS type. There were no substantial differences in refractive error between MPS II and MPS VI. CONCLUSION: In our patients, CCT in MPS II and VI did not differ statistically significantly from age-related values found in healthy subjects. Thus, intraocular pressure readings detected by applanation tonometry in MPS II and VI in the majority of patients can be regarded as reliable. In the case of clinically marked corneal clouding, measurement of CCT is recommended to adequately assess intraocular pressure and possible coexistent glaucoma.

Findings in the anterior segment on ultrasound biomicroscopy in Maroteaux-Lamy syndrome.

PURPOSE: Maroteaux-Lamy syndrome is one of the mucopolysaccharidoses caused by enzyme deficiency (arylsulfatase B) that leads to incomplete degradation and storage of dermatan sulfate. We report a case of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) with corneal involvement and introduce ultrasound biomicroscopy (UBM) as an examination with which to follow disease progression in relation to deposition in cornea, angle, and iris. METHODS: We describe a 11-year-old boy with a clinical and laboratorial diagnosis of MPS VI who developed increasing bilateral corneal opacification and decreased visual acuity. He underwent two seriate UBM (50-MHz transducer) evaluations. RESULTS: UBM examination showed diffuse and homogeneous stromal hyper-reflective deposit in both eyes and an increase in peripheral corneal thickness throughout time. CONCLUSION: High-frequency ultrasound documentation of corneal deposit and anterior segment involvement in a patient with Maroteaux-Lamy syndrome is unique, and follow-up revealed thickening of the corneal periphery, which may be related to the progression of the disease (continuous mucopolysaccharide deposits in corneal stroma). UBM was used to locate and document the deposit, as well as to accompany the deposit's evolution, characterizing corneal changes and angle structure involvement.

Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI): long-term follow-up.

We describe the results of bone marrow transplantation (BMT) in four patients with mucopolysaccharidosis type VI (MPS VI, McKusick 253200)--Maroteaux-Lamy disease. The indications for transplantation were cardiomyopathy in three patients and severe obstructive sleep apnoea in one. The follow-up period ranges between 1 and 9 years, and three of the patients are at mainstream schools. In all of the patients the facial features have become less coarse and the cardiac manifestations have improved or remained stable. However, skeletal changes have persisted or even progressed, although posture and joint mobility have improved and all the patients have remained ambulatory and active. BMT appears to prolong survival and improve the quality of life in MPS VI patients, but careful selection of patients is essential.